Abstract/Summary Neisseria gonorrhoeae has re-emerged as a global public health concern as it causes roughly 100 million new infections each year and isolates have emerged that are resistant to all clinically-relevant antibiotics; these alarming trends have prompted the US Center for Disease Control to name N. gonorrhoeae as one of three `urgent' microbial threats. The success of N. gonorrhoeae is attributable in part to its capacity to colonize the female genital tract without obvious clinical manifestation, allowing it to persist undetected as it is spread to sexual partners. Consistent with this, N. gonorrhoeae does not express factors with overt virulent potential. Instead, it exhibits a lifestyle intent on avoiding and actively subverting immune detection, and expresses elegant systems to access highly restricted nutrient stores to support its growth within human tissues. This translational research program will exploit our recent success in targeting the receptor proteins that allow N. gonorrhoeae to acquire iron and zinc during infection; these trace metals are essential for life but effectively absent in mammalian tissues due to a process known as `nutritional immunity'. We have unexpectedly discovered that the bacterial surface-exposed receptor proteins that bind the host iron sequestering-serum protein transferrin does not elicit a protective immune response because it rapidly binds transferrin in the tissues, and that we can overcome this deficit by generating a point mutant that is structurally identical except that it does not bind transferrin. We will use this approach to generate immunogens that target alternative iron and zinc acquisition systems of N. gonorrhoeae, and then produce a multicomponent vaccine that elicits an immune response that will simultaneously starve the bacteria of these two essential nutrients and kill the bacteria through classical antibody-dependent activities. Along with this directly translational pursuit, we will also perform community outreach studies to understand the potential resistance to gonococcal vaccines among different stakeholder populations and reveal potential strategies to overcome these barriers. Then, our genomic and phenotypic analysis of the global diversity of the receptor systems that we are targeting will be integrated with global gonococcal epidemiology data and the understanding gained through our community-based studies to make informed predictions about the potential impact of different vaccine formulation and public health-focused implementation strategies on the global prevalence of N. gonorrhoeae. When complete, this program will therefore deliver a vaccine formulation that targets distinct but equally essential nutrient uptake pathways to confer sterilizing immunity against gonococcal infection and will provide actionable information that will guide the eventual implementation of this vaccine in a manner that will ultimately allow eradication of this devastating human-restricted pathogen.